Limits...
Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.

Antony P, Vijayan R - Drug Des Devel Ther (2016)

Bottom Line: Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers.Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1.These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.

ABSTRACT
Apoptosis is a highly regulated process crucial for maintaining cellular homeostasis and development. The B-cell lymphoma 2 (Bcl-2) family of proteins play a crucial role in regulating apoptosis. Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers. Annona muricata is a tropical plant that belongs to the Annonaceae family and is well known for its anticancer properties. In this study, molecular docking and simulations were performed to investigate the inhibitory potential of phytochemicals present in A. muricata against antiapoptotic proteins of the Bcl-2 family including Bcl-2, B-cell lymphoma extra-large (Bcl-Xl), and Mcl-1. Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1. Binding score and interactions of these acetogenins were notably better than those of currently available synthetic and natural inhibitors. Molecular dynamics simulations of the top-scoring lead molecules established that these molecules could bind strongly and consistently in the active site of Bcl-Xl. These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

No MeSH data available.


Related in: MedlinePlus

Binding interactions of acetogenins in the active site of Bcl-Xl (4QVX).Notes: (A) Bcl-Xl protein structure with the region shown in (B–F) boxed in red. Interaction of Bcl-Xl with (B) annomuricin A, (C) annohexocin, (D) muricatocin A, (E) annomuricn-D-one, and (F) muricatetrocin A/B.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4835113&req=5

f3-dddt-10-1399: Binding interactions of acetogenins in the active site of Bcl-Xl (4QVX).Notes: (A) Bcl-Xl protein structure with the region shown in (B–F) boxed in red. Interaction of Bcl-Xl with (B) annomuricin A, (C) annohexocin, (D) muricatocin A, (E) annomuricn-D-one, and (F) muricatetrocin A/B.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.

Mentions: The 3D structure of antiapoptotic/prosurvival protein Bcl-Xl (4QVX and 3ZLR) consists of a common domain formed by assembling two hydrophobic (α5 and α6; Figure S2) and six amphipathic α helices (α1–α4, α7, and α8).64 Four amphipathic helices fold to form a long hydrophobic groove of nearly 20 Å in length (Figure S1A). Structural insights reveal that high-affinity binding of proapoptotic protein, and BH3-only proteins is mediated by interactions in the P2 and P4 pockets of the hydrophobic groove and also by electrostatic interactions between conserved arginine and aspartic acid residues of proapoptotic and prosurvival proteins, respectively.24,52 The P2 and P4 pockets are lined by residues Glu96, Tyr101, Ser106, Asp107, Leu108, Arg139, and Tyr195.24 The P2 hydrophobic pocket is crucial for tight binding of ligand molecules due to its deep and plastic cavity.65 Analysis of the binding pose of annomuricin A in 3ZLR showed that it interacted with the protein by forming six hydrogen bonds and numerous hydrophobic interactions with the critical residues seen in the active site. Annomuricin A is present in the leaves and pericarp of A. muricata, and it has an α,β-unsaturated-γ-lactone moiety and a mono-THF ring with five hydroxyl groups (Figure 1A).28,66 The α,β-unsaturated-γ-lactone moiety of annomuricin A was buried in the P2 pocket, and the hydroxyl group adjacent to this moiety formed a hydrogen bond with the important Ser106 in the P2 pocket that is required for tight binding (Figure S1B).65 The remaining four hydroxyl groups in this molecule interacted with Arg132, Asp133, Asn136, and Arg139 by forming hydrogen bonds. The long hydrophobic tail of the molecule extended into the P4 pocket and formed interactions with several hydrophobic residues, including Tyr101 and Tyr195 (Figures 2B and S3A).24 Entropic penalty imposed by restraining the ligand in the binding site was overcome by the highly favorable lipophilic and hydrogen-bond interactions in the binding site. A similar binding pattern was also observed in the 4QVX–annomuricin A complex. The hydroxyl groups adjacent to the THF ring region and the alkyl chain formed hydrogen bonds with the key residues such as Ser106, Leu108, and Leu130 in the pockets (Figures 3B and S4A). In the two Bcl-Xl structures considered, annomuricin A exhibited GlideScores of −13.00 kcal/mol and −12.59 kcal/mol, respectively. Numerous hydrophobic contacts contributed to its binding to Bcl-Xl (Figures S3A and S4A).


Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.

Antony P, Vijayan R - Drug Des Devel Ther (2016)

Binding interactions of acetogenins in the active site of Bcl-Xl (4QVX).Notes: (A) Bcl-Xl protein structure with the region shown in (B–F) boxed in red. Interaction of Bcl-Xl with (B) annomuricin A, (C) annohexocin, (D) muricatocin A, (E) annomuricn-D-one, and (F) muricatetrocin A/B.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835113&req=5

f3-dddt-10-1399: Binding interactions of acetogenins in the active site of Bcl-Xl (4QVX).Notes: (A) Bcl-Xl protein structure with the region shown in (B–F) boxed in red. Interaction of Bcl-Xl with (B) annomuricin A, (C) annohexocin, (D) muricatocin A, (E) annomuricn-D-one, and (F) muricatetrocin A/B.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
Mentions: The 3D structure of antiapoptotic/prosurvival protein Bcl-Xl (4QVX and 3ZLR) consists of a common domain formed by assembling two hydrophobic (α5 and α6; Figure S2) and six amphipathic α helices (α1–α4, α7, and α8).64 Four amphipathic helices fold to form a long hydrophobic groove of nearly 20 Å in length (Figure S1A). Structural insights reveal that high-affinity binding of proapoptotic protein, and BH3-only proteins is mediated by interactions in the P2 and P4 pockets of the hydrophobic groove and also by electrostatic interactions between conserved arginine and aspartic acid residues of proapoptotic and prosurvival proteins, respectively.24,52 The P2 and P4 pockets are lined by residues Glu96, Tyr101, Ser106, Asp107, Leu108, Arg139, and Tyr195.24 The P2 hydrophobic pocket is crucial for tight binding of ligand molecules due to its deep and plastic cavity.65 Analysis of the binding pose of annomuricin A in 3ZLR showed that it interacted with the protein by forming six hydrogen bonds and numerous hydrophobic interactions with the critical residues seen in the active site. Annomuricin A is present in the leaves and pericarp of A. muricata, and it has an α,β-unsaturated-γ-lactone moiety and a mono-THF ring with five hydroxyl groups (Figure 1A).28,66 The α,β-unsaturated-γ-lactone moiety of annomuricin A was buried in the P2 pocket, and the hydroxyl group adjacent to this moiety formed a hydrogen bond with the important Ser106 in the P2 pocket that is required for tight binding (Figure S1B).65 The remaining four hydroxyl groups in this molecule interacted with Arg132, Asp133, Asn136, and Arg139 by forming hydrogen bonds. The long hydrophobic tail of the molecule extended into the P4 pocket and formed interactions with several hydrophobic residues, including Tyr101 and Tyr195 (Figures 2B and S3A).24 Entropic penalty imposed by restraining the ligand in the binding site was overcome by the highly favorable lipophilic and hydrogen-bond interactions in the binding site. A similar binding pattern was also observed in the 4QVX–annomuricin A complex. The hydroxyl groups adjacent to the THF ring region and the alkyl chain formed hydrogen bonds with the key residues such as Ser106, Leu108, and Leu130 in the pockets (Figures 3B and S4A). In the two Bcl-Xl structures considered, annomuricin A exhibited GlideScores of −13.00 kcal/mol and −12.59 kcal/mol, respectively. Numerous hydrophobic contacts contributed to its binding to Bcl-Xl (Figures S3A and S4A).

Bottom Line: Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers.Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1.These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.

ABSTRACT
Apoptosis is a highly regulated process crucial for maintaining cellular homeostasis and development. The B-cell lymphoma 2 (Bcl-2) family of proteins play a crucial role in regulating apoptosis. Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers. Annona muricata is a tropical plant that belongs to the Annonaceae family and is well known for its anticancer properties. In this study, molecular docking and simulations were performed to investigate the inhibitory potential of phytochemicals present in A. muricata against antiapoptotic proteins of the Bcl-2 family including Bcl-2, B-cell lymphoma extra-large (Bcl-Xl), and Mcl-1. Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1. Binding score and interactions of these acetogenins were notably better than those of currently available synthetic and natural inhibitors. Molecular dynamics simulations of the top-scoring lead molecules established that these molecules could bind strongly and consistently in the active site of Bcl-Xl. These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

No MeSH data available.


Related in: MedlinePlus